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1.  Portulaca oleracea L.: A Review of Phytochemistry and Pharmacological Effects 
BioMed Research International  2015;2015:925631.
Portulaca oleracea L., belonging to the Portulacaceae family, is commonly known as purslane in English and Ma-Chi-Xian in Chinese. It is a warm-climate, herbaceous succulent annual plant with a cosmopolitan distribution. It is eaten extensively as a potherb and added in soups and salads around the Mediterranean and tropical Asian countries and has been used as a folk medicine in many countries. Diverse compounds have been isolated from Portulaca oleracea, such as flavonoids, alkaloids, polysaccharides, fatty acids, terpenoids, sterols, proteins vitamins and minerals. Portulaca oleracea possesses a wide spectrum of pharmacological properties such as neuroprotective, antimicrobial, antidiabetic, antioxidant, anti-inflammatory, antiulcerogenic, and anticancer activities. However, few molecular mechanisms of action are known. This review provides a summary of phytochemistry and pharmacological effects of this plant.
PMCID: PMC4321094
2.  Off Target Effects of c-MET Inhibitors on Thyroid Cancer Cells 
Molecular cancer therapeutics  2013;13(1):134-143.
Aberrantly activated c-MET signaling occurs in several cancers, promoting the development of c-MET inhibitors. In this study, we found that eight of 8 thyroid cancer cell lines (including six anaplastic thyroid cell lines) have prominent expression of c-MET protein. Fifty percent of the thyroid cancer cell lines (four of 8) were growth-inhibited by two small molecule c-MET inhibitors (Tivantinib and Crizotinib), associated with apoptosis and G2/M cell cycle arrest. However, Crizotinib did not inhibit 50% proliferation of thyroid cancer cells (SW1736 and TL3) at a concentration at which the drug completely inhibited ligand-stimulated c-MET phosphorylation. On the other hand, Tivantinib was less potent than Crizotinib at inhibiting c-MET phosphorylation, but was more potent than Crizotinib at decreasing cell growth. Suppressing c-MET protein expression and phosphorylation using siRNA targeting c-MET did not induce cell cycle arrest and apoptosis. Taken together, Tivantinib and Crizotinib have off target(s) activity, contributing to their anti-tumor activity. In vivo study showed that Crizotinib markedly inhibited the growth of thyroid cancer cells (SW1736) in immunodeficient mice. In summary, c-MET inhibitors (Tivantinib and Crizotinib) suppress the growth of aggressive thyroid cancer cells, and this potential therapeutic benefit results from their non-MET-targeting effects.
PMCID: PMC3947168  PMID: 24170771
c-MET; thyroid cancer; Crizotinib; Tivantinib; off-target
3.  Will There Be a Vaccine to Prevent HCV Infection? 
Seminars in liver disease  2014;34(1):79-88.
Prevention of hepatitis C virus (HCV) infection by vaccination has been a priority since discovery of the virus and the need has not diminished over the past 25 years. Infection rates are increasing in developed countries because of intravenous drug use. Reducing transmission will be difficult without a vaccine to prevent persistence of primary infections, and also secondary infections that may occur after cure of chronic hepatitis C with increasingly effective direct-acting antiviral (DAA) regimens. Vaccine need is also acute in resource poor countries where most new infections occur and DAAs may be unaffordable. Spontaneous resolution of HCV infection confers durable protection, but mechanisms of immunity remain obscure and contested in the context of vaccine design. A vaccine must elicit a CD4+ helper T cell response that does not fail during acute infection. The need for neutralizing antibodies versus cytotoxic CD8+ T cells is unsettled and reflected in the design of two very different vaccines evaluated in humans for safety and immunogenicity. Here we review the status of vaccine development and the scientific and practical challenges that must be met if the burden of liver disease caused by HCV is to be reduced or eliminated.
PMCID: PMC4278371  PMID: 24782261
hepatitis C virus; vaccine; direct acting antiviral; persistent infection
4.  HPMA copolymer-based combination therapy toxic to both prostate cancer stem/progenitor cells and differentiated cells induces durable anti-tumor effects 
Current treatments for prostate cancer are still not satisfactory, often resulting in tumor regrowth and metastasis. One of the main reasons for the ineffective anti-prostate cancer treatments is the failure to deplete cancer stem-like cells (CSCs) - a subset of cancer cells with enhanced tumorigenic capacity. Thus, combination of agents against both CSCs and bulk tumor cells may offer better therapeutic benefits. Several molecules with anti-cancer stem/progenitor cell activities have been under preclinical evaluations. However, their low solubility and nonspecific toxicity limit their clinical translation. Herein, we designed a combination macromolecular therapy containing two drug conjugates: HPMA copolymer-cyclopamine conjugate (P-CYP) preferentially toxic to cancer stem/progenitor cells, and HPMA copolymer-docetaxel conjugate (P-DTX) effective in debulking the tumor mass. Both conjugates were synthesized using RAFT (reversible addition-fragmentation chain transfer) polymerization resulting in narrow molecular weight distribution. The killing effect of the two conjugates against bulk tumor cells and CSCs were evaluated in vitro and in vivo. In PC-3 or RC-92a/hTERT prostate cancer cells, P-CYP preferentially kills and impairs the function of CD133+ prostate cancer stem/progenitor cells; P-DTX was able to kill bulk tumor cells instead of CSCs. In PC-3 xenograft mice model, combination of P-DTX and P-CYP showed the most effective and persistent tumor growth inhibitory effect. In addition, residual tumors contained less CD133+ cancer cells following combination or P-CYP treatments, indicating selective killing of cancer cells with stem/progenitor cell properties.
PMCID: PMC3858468  PMID: 24041709
N-(2-hydroxypropyl)methacrylamide (HPMA); Combination therapy; Cancer stem/progenitor cells; Cyclopamine; Docetaxel
5.  Impact of Groundwater Table and Plateau Zokors (Myospalax baileyi) on Ecosystem Respiration in the Zoige Peatlands of China 
PLoS ONE  2014;9(12):e115542.
Peatlands contain large amount of carbon stock that is vulnerable to release into the atmosphere. Mostly because of human impact, the peatlands at Zoige Wetlands face severe degradation, and the groundwater table is now lower than before, which has increased the population of the plateau zokor, a burrowing rodent. However, the impact of these changes on ecosystem carbon flows has not been studied. To investigate how the plateau zokor and the groundwater level alter the ecosystem respiration of the Zoige peatlands, we sampled the CO2 flux of hummocks shaped by the zokors and compared it with the CO2 flux of undisturbed sites with different groundwater table levels. The soil organic carbon (SOC), soil water content (SWC) and soil temperature at 5 cm (T5) were measured. SOC showed no significant difference among the four sampling sites and did not correlate with the CO2 flux, while SWC was found to partly determine the CO2 flux. A linear equation could adequately describe the relationship between the natural logarithm of the ecosystem respiration and the soil temperature. It is demonstrated that descending groundwater table might accelerate ecosystem respiration and the CO2 flux from hummocks was higher than the CO2 flux from the control site in the non-growing season. With rising temperature, the CO2 flux from the control site accelerated faster than that from the hummocks. Our results show that ecosystem respiration was significantly lower from hummocks than at the control site in the growing season. The results on the impact of zokors on greenhouse gas emissions presented in this paper provide a useful reference to help properly manage not only this, but other litter-burrowing mammals at peatland sites.
PMCID: PMC4277300  PMID: 25542023
6.  Intervention of transforming pulmonary fibrosis with NF-κB p65 antisense oligonucleotide 
Objective: NF-κB, especially p65 subunit, plays important role in the process of pulmonary fibrosis. In this study, we transformed fibroblast into myofibroblast induced by bleomycin, and then studied the effects of NF-κB p65 antisense oligonucleotide on pulmonary fibrosis in mouse model. Methods: Pulmonary fibrosis was induced by bleomycin in C57BL/6 mouse (modeling group). The NF-κB antisense oligonucleotide was injected intravenously into mouse 6 hours before inducing (test group), we performed broncho-alveolar lavage and blood collecting through cardiac puncture. Bronchoalveolar Lavage Fluid (BALF) and serum from normal C57BL/6 mouse (control group) were collected for comparison. Immunohistochemistry staining of the NF-κB and α-SMA on lung tissues and cultured cells were carried out in each group, respectively. Results: The expression level of NF-κB and α-SMA were both consistently higher in modeling group when compared with control group (P < 0.05). Meanwhile, they were reduced significantly through the intervention of NF-κB p65 antisense oligonucleotide in the test group (P < 0.05). More importantly, the expression of NF-κB was positively correlated with α-SMA. Conclusion: our study suggests the potential in prevention of bleomycin-induced pulmonary fibrosis with NF-κB p65 antisense oligonucleotide.
PMCID: PMC4307475  PMID: 25664028
Fibroblast; myofibroblast; NF-κB; α-SMA; antisense oligonucleotide
8.  Effect of extractions from Ephedra sinica Stapf on hyperlipidemia in mice 
The aim of the present study was to investigate the hypolipidemic and antioxidant potential of ephedra extractions in diet-induced hyperlipidemic mice. Mice were fed a diet high in fat to establish the hyperlipidemic model. A total of 48 mice were randomly divided into six groups, which included the normal control, model control, positive control, ephedra alkaloid, ephedra polysaccharide and ephedra non-alkaloid groups. Intragastric administration of the respective treatments was provided continuously for four weeks and the body weight was recorded weekly. The total levels of cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and malondialdehyde (MDA), and the activity levels of superoxide dismutase (SOD), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum were recorded. In addition, changes in liver morphology and organ coefficients (ratio of organ to body weight) were evaluated, while the acute toxicity reactions of ephedra extractions were investigated using the modified Spearman-Karber method. Compared with the mice in the model control group, the weight, liver coefficient, serum levels of TC, TG and MDA, and activities of ALT and AST were significantly lower (P<0.05) in the mice in the ephedra non-alkaloid group. However, the level of HDL-C and the activity of SOD were markedly higher (P<0.05). Fatty degeneration of the liver in the ephedra alkaloid and non-alkaloid groups was notably improved compared with the model control group. The mean lethal dose (LD50) of ephedra alkaloids was 610 mg/kg, and the maximum tolerated dose of oral ephedra non-alkaloids in the mice was 367.5-fold larger than the clinical dosage in humans. In conclusion, ephedra non-alkaloids have therapeutic potential for the treatment of hyperlipidemia, since they are able to improve lipid metabolism and are relatively safe for use under the maximum tolerated dose.
PMCID: PMC4280985  PMID: 25574244
ephedra alkaloids; ephedra polysaccharides; ephedra non-alkaloids; hyperlipidemia; acute toxicity
9.  Construction and Characterization of Three Wheat Bacterial Artificial Chromosome Libraries 
We have constructed three bacterial artificial chromosome (BAC) libraries of wheat cultivar Triticum aestivum Wangshuibai, germplasms T. monococcum TA2026 and TA2033. A total of 1,233,792,170,880 and 263,040 clones were picked and arrayed in 384-well plates. On the basis of genome sizes of 16.8 Gb for hexaploid wheat and 5.6 Gb for diploid wheat, the three libraries represented 9.05-, 2.60-, and 3.71-fold coverage of the haploid genomes, respectively. An improved descending pooling system for BAC libraries screening was established. This improved strategy can save 80% of the time and 68% of polymerase chain reaction (PCR) with the same successful rate as the universal 6D pooling strategy.
PMCID: PMC4284684  PMID: 25464379
bacterial artificial chromosome; wheat; descending pool
10.  Expression of TWIST, an inducer of epithelial-mesenchymal transition, in nasopharyngeal carcinoma and its clinical significance 
Epithelial-mesenchymal transition (EMT) has been implicated in the development of a number of cancers. An important EMT inducer, TWIST, has been detected to be over-expressed in a variety of tumors, but rarely been studied in nasopharyngeal carcinoma (NPC). This study aimed to examine TWIST expression and its association with clinicopathological factors and prognosis in NPC. A total of 65 NPC and 20 normal samples were involved in the present study. RT-PCR and immunohistochemistry were used to examine the mRNA and protein expressions of TWIST in NPC and normal tissues. The relationship of TWIST expression levels with clinical features and prognosis of NPC patients were analyzed. The positive rate of TWIST expression was markedly higher in NPC tissues than that in normal tissues. Over-expression of TWIST was correlated with N stage and the presence of distant metastasis. Patients with positive TWIST expression had a significantly shorter overall survival time relative to patients with negative TWIST expression. The data suggest that TWIST over-expression has a correlation with lymphatic and distant metastasis in NPC. Moreover, it might be a novel biomarker for prediction of advanced tumor progression and a potential unfavorable prognostic factor as well as a potential treatment target for NPC.
PMCID: PMC4314002
Nasoparyangeal carcinoma; TWIST; expression; inmmunohistochemistry; prognosis
11.  Immunomodulatory Effects of Polysaccharide from Marine Fungus Phoma herbarum YS4108 on T Cells and Dendritic Cells 
Mediators of Inflammation  2014;2014:738631.
YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungus Phoma herbarum YS4108, has great antitumor potential via enhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-) γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γ production through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II) via TLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.
PMCID: PMC4267005  PMID: 25525304
12.  3D Dynamic Culture of Rabbit Articular Chondrocytes Encapsulated in Alginate Gel Beads Using Spinner Flasks for Cartilage Tissue Regeneration 
BioMed Research International  2014;2014:539789.
Cell-based therapy using chondrocytes for cartilage repair suffers from chondrocyte dedifferentiation. In the present study, the effects of an integrated three-dimensional and dynamic culture on rabbit articular chondrocytes were investigated. Cells (passages 1 and 4) were encapsulated in alginate gel beads and cultured in spinner flasks in chondrogenic and chondrocyte growth media. Subcutaneous implantation of the cell-laden beads was performed to evaluate the ectopic chondrogenesis. It was found that cells remained viable after 35 days in the three-dimensional dynamic culture. Passage 1 cells demonstrated a proliferative growth in both media. Passage 4 cells showed a gradual reduction in DNA content in growth medium, which was attenuated in chondrogenic medium. Deposition of glycosaminoglycans (GAG) was found in all cultures. While passage 1 cells generally produced higher amounts of GAG than passage 4 cells, GAG/DNA became similar on day 35 for both cells in growth media. Interestingly, GAG/DNA in growth medium was greater than that in chondrogenic medium for both cells. Based on GAG quantification and gene expression analysis, encapsulated passage 1 cells cultured in growth medium displayed the best ectopic chondrogenesis. Taken together, the three-dimensional and dynamic culture for chondrocytes holds great potential in cartilage regeneration.
PMCID: PMC4260432  PMID: 25506593
13.  Spatial organization of transcription machinery and its segregation from the replisome in fast-growing bacterial cells 
Nucleic Acids Research  2014;42(22):13696-13705.
In a fast-growing Escherichia coli cell, most RNA polymerase (RNAP) is allocated to rRNA synthesis forming transcription foci at clusters of rrn operons or bacterial nucleolus, and each of the several nascent nucleoids contains multiple pairs of replication forks. The composition of transcription foci has not been determined. In addition, how the transcription machinery is three-dimensionally organized to promote cell growth in concord with replication machinery in the nucleoid remains essentially unknown. Here, we determine the spatial and functional landscapes of transcription and replication machineries in fast-growing E. coli cells using super-resolution-structured illumination microscopy. Co-images of RNAP and DNA reveal spatial compartmentation and duplication of the transcription foci at the surface of the bacterial chromosome, encompassing multiple nascent nucleoids. Transcription foci cluster with NusA and NusB, which are the rrn anti-termination system and are associated with nascent rRNAs. However, transcription foci tend to separate from SeqA and SSB foci, which track DNA replication forks and/or the replisomes, demonstrating that transcription machinery and replisome are mostly located in different chromosomal territories to maintain harmony between the two major cellular functions in fast-growing cells. Our study suggests that bacterial chromosomes are spatially and functionally organized, analogous to eukaryotes.
PMCID: PMC4267616  PMID: 25416798
14.  Different Resting-State Functional Connectivity Alterations in Smokers and Nonsmokers with Internet Gaming Addiction 
BioMed Research International  2014;2014:825787.
This study investigated changes in resting-state functional connectivity (rsFC) of posterior cingulate cortex (PCC) in smokers and nonsmokers with Internet gaming addiction (IGA). Twenty-nine smokers with IGA, 22 nonsmokers with IGA, and 30 healthy controls (HC group) underwent a resting-state fMRI scan. PCC connectivity was determined in all subjects by investigating synchronized low-frequency fMRI signal fluctuations using a temporal correlation method. Compared with the nonsmokers with IGA, the smokers with IGA exhibited decreased rsFC with PCC in the right rectus gyrus. Left middle frontal gyrus exhibited increased rsFC. The PCC connectivity with the right rectus gyrus was found to be negatively correlated with the CIAS scores in the smokers with IGA before correction. Our results suggested that smokers with IGA had functional changes in brain areas related to motivation and executive function compared with the nonsmokers with IGA.
PMCID: PMC4255056  PMID: 25506057
15.  Genome-wide siRNA screen reveals a new cellular partner of NK cell receptor KIR2DL4: heparan sulfate directly modulates KIR2DL4-mediated responses 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(10):10.4049/jimmunol.1302079.
KIR2DL4 (CD158d) is a distinct member of the killer cell Ig-like receptor (KIR) family in human NK cells that can induce cytokine production and cytolytic activity in resting NK cells. Soluble HLA-G, normally expressed only by fetal-derived trophoblast cells, was reported to be a ligand for KIR2DL4; however, KIR2DL4 expression is not restricted to the placenta and can be found in CD56high subset of peripheral blood NK cells. We demonstrated that KIR2DL4 can interact with alternative ligand(s), expressed by cells of epithelial or fibroblast origin. A genome-wide high-throughput siRNA screen revealed that KIR2DL4 recognition of cells surface ligand(s) is directly regulated by heparan sulfate (HS) glucosamine 3-O-sulfotransferase 3B1 (HS3ST3B1). KIR2DL4 was found to directly interact with HS/heparin, and the D0-domain of KIR2DL4 was essential for this interaction. Accordingly, exogenous HS/heparin can regulate cytokine production by KIR2DL4-expressing NK cells and HEK293T cells (HEK293T-2DL4) and induces differential localization of KIR2DL4 to rab5+ and rab7+ endosomes, thus leading to down-regulation of cytokine production and degradation of the receptor. Furthermore, we showed that intimate interaction of syndecan-4 (SDC4) HS Proteo-Glycan (HSPG) and KIR2DL4 directly affects receptor endocytosis and membrane trafficking.
PMCID: PMC3836631  PMID: 24127555
16.  Role of RNA Polymerase in the Organization of the Bacterial Nucleoid 
Chemical reviews  2013;113(11):10.1021/cr4001429.
PMCID: PMC3830623  PMID: 23941620
17.  Capacitance effect on the oscillation and switching characteristics of spin torque oscillators 
Nanoscale Research Letters  2014;9(1):597.
We have studied the capacitance effect on the oscillation characteristics and the switching characteristics of the spin torque oscillators (STOs). We found that when the external field is applied, the STO oscillation frequency exhibits various dependences on the capacitance for injected current ranging from 8 to 20 mA. The switching characteristic is featured with the emerging of the canted region; the canted region increases with the capacitance. When the external field is absent, the STO free-layer switching time exhibits different dependences on the capacitance for different injected current. These results help to establish the foundation for capacitance-involved STO modeling.
PMCID: PMC4230906  PMID: 25404870
Capacitance effect; Oscillation frequency; Canted region; Switching time
18.  DhhP, a Cyclic di-AMP Phosphodiesterase of Borrelia burgdorferi, Is Essential for Cell Growth and Virulence 
Infection and Immunity  2014;82(5):1840-1849.
Cyclic di-AMP (c-di-AMP) is a recently discovered second messenger in bacteria. Most of work on c-di-AMP signaling has been done in Gram-positive bacteria, firmicutes, and actinobacteria, where c-di-AMP signaling pathways affect potassium transport, cell wall structure, and antibiotic resistance. Little is known about c-di-AMP signaling in other bacteria. Borrelia burgdorferi, the causative agent of Lyme disease, is a spirochete that has a Gram-negative dual membrane. In this study, we demonstrated that B. burgdorferi BB0619, a DHH-DHHA1 domain protein (herein designated DhhP), functions as c-di-AMP phosphodiesterase. Recombinant DhhP hydrolyzed c-di-AMP to pApA in a Mn2+- or Mg2+-dependent manner. In contrast to c-di-AMP phosphodiesterases reported thus far, DhhP appears to be essential for B. burgdorferi growth both in vitro and in the mammalian host. Inactivation of the chromosomal dhhP gene could be achieved only in the presence of a plasmid-encoded inducible dhhP gene. The conditional dhhP mutant had a dramatic increase in intracellular c-di-AMP level in comparison to the isogenic wild-type strain. Unlike what has been observed in Gram-positive bacteria, elevated cellular c-di-AMP in B. burgdorferi did not result in an increased resistance to β-lactamase antibiotics, suggesting that c-di-AMP's functions in spirochetes differ from those in Gram-positive bacteria. In addition, the dhhP mutant was defective in induction of the σS factor, RpoS, and the RpoS-dependent outer membrane virulence factor OspC, which uncovers an important role of c-di-AMP in B. burgdorferi virulence.
PMCID: PMC3993442  PMID: 24566626
19.  T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against LMP1-positive nasopharyngeal carcinoma cells in vitro and in vivo 
Journal of Biomedical Research  2014;28(6):468-475.
T cells modified with chimeric antigen receptor are an attractive strategy to treat Epstein-Barr virus (EBV) associated malignancies. The EBV latent membrane protein 1 (LMP1) is a 66-KD integral membrane protein encoded by EBV that consists of transmembrane-spanning loops. Previously, we have identified a functional signal chain variable fragment (scFv) that specifically recognizes LMP1 through phage library screening. Here, we constructed a LMP1 specific chimeric antigen receptor containing anti-LMP1 scFv, the CD28 signalling domain, and the CD3ζ chain (HELA/CAR). We tested its functional ability to target LMP1 positive nasopharyngeal carcinoma cells. HELA/CAR cells were efficiently generated using lentivirus vector encoding the LMP1-specific chimeric antigen receptor to infect activated human CD3+ T cells. The HELA/CAR T cells displayed LMP1 specific cytolytic action and produced IFN-γ and IL-2 in response to nasopharyngeal carcinoma cells overexpressing LMP1. To demonstrate in vivo anti-tumor activity, we tested the HELA/CAR T cells in a xenograft model using an LMP1 overexpressing tumor. Intratumoral injection of anti-LMP1 HELA/CAR-T cells significantly reduced tumor growth in vivo. These results show that targeting LMP1 using HELA/CAR cells could represent an alternative therapeutic approach for patients with EBV-positive cancers.
PMCID: PMC4250525  PMID: 25469116
chimeric antigen receptor; LMP1; nasopharyngeal carcinoma; EBV; adoptive T cell therapy
20.  Ellman’s reagent in promoting crystallization and structure determination of Anabaena CcbP 
Acta Crystallographica Section F  2012;68(Pt 11):1409-1414.
Ellman’s reagent oxidized the free sulfhydryl group of cysteine in Anabaena CcbP protein, facilitating its crystallization.
Obtaining crystals presented a bottleneck in the structural study of Anabaena cyanobacterial Ca2+-binding protein (CcbP). In this report, the promoting effect of Ellman’s reagent [5,5′-dithiobis(2-nitrobenzoic acid); DTNB] on the crystallization of CcbP is described. CcbP contains one free cysteine. A quick and simple oxidation reaction with DTNB blocked the free cysteine in purified CcbP and generated a homogenous monomeric protein for crystallization. The crystal structure of DTNB-modified CcbP was determined by the single-wavelength anomalous diffraction method. Structure analysis indicated that DTNB modification facilitated crystallization of CcbP by inducing polar inter­actions in the crystal lattice. DTNB-mediated cysteine modification was demonstrated to have little effect on the overall structure and the Ca2+ binding of CcbP. Thus, DTNB modification may provide a simple and general approach for protein modification to improve the success of crystallization screening.
PMCID: PMC3515393  PMID: 23143261
Ellman’s reagent; chemical modification; Anabaena CcbP
21.  Effects of voluntary alcohol drinking on corticotropin-releasing factor and preprodynorphin mRNA levels in the central amygdala of Sardinian alcohol-preferring rats 
Neuroscience letters  2013;554:10.1016/j.neulet.2013.08.071.
The stress-response corticotropin-releasing factor (CRF) and dynorphin systems are critically involved in alcohol drinking and “anxiety” ”-related behaviors. Selectively bred Sardinian alcohol-preferring (sP) rats display high inherent “anxiety”-related behaviors, in comparison with their alcohol-non preferring counterpart (sNP rats). The present study was undertaken to investigate: (1) if there were genetically determined differences in basal gene expression levels of CRF, CRF-R1, preprodynorphin (ppDyn) and kappa opioid receptor (KOP-r) between sP and sNP rats; specifically, mRNA levels of the above genes were measured in the central amygdala (CeA), hypothalamus and other stress responsive and mesolimbic regions of alcohol-naive sP and sNP rats; and (2) if the above mRNA levels were altered by voluntary alcohol drinking in sP rats exposed to the standard, homecage 2-bottle “alcohol vs water” choice regimen 24 hours/day for 17 days. Higher basal CRF mRNA levels were found only in CeA of alcohol-naive sP rats, compared with sNP rats; these levels were decreased after alcohol consumption. In contrast, ppDyn mRNA levels in CeA of sP rats were increased by alcohol consumption, but with no basal difference from sNP rats. Although higher basal ppDyn mRNA levels were found in hypothalamus of sP rats, compared with sNP rats, there was no alteration after alcohol drinking in sP rats. No difference for the above mRNA levels was observed in other regions, including nucleus accumbens shell or core, caudate-putamen, ventral tegmental area and medial/basolateral amygdala, between the two rat lines before or after alcohol consumption. Our results demonstrate the existence of genetically determined high basal CRF mRNA levels in CeA of sP rats. Alcohol consumption decreased CeA CRF mRNA levels with parallel increases in CeA ppDyn mRNA levels.
PMCID: PMC3825761  PMID: 24021806
corticotropin-releasing factor; preprodynorphin; central amygdala; alcohol drinking; Sardinian alcohol-preferring (sP) and -non preferring (sNP) rats; gene expression
22.  Assessment of in vivo microstructure alterations in gray matter using DKI in internet gaming addiction 
The aim of the current study was to investigate the utility of diffusional kurtosis imaging (DKI) in the detection of gray matter (GM) alterations in people suffering from Internet Gaming Addiction (IGA).
DKI was applied to 18 subjects with IGA and to 21 healthy controls (HC). Whole-brain voxel-based analyses were performed with the following derived parameters: mean kurtosis metrics (MK), radial kurtosis (K⊥), and axial kurtosis (K//). A significance threshold was set at P <0.05, AlphaSim corrected. Pearson’s correlation was performed to investigate the correlations between the Chen Internet Addiction Scale (CIAS) and the DKI-derived metrics of regions that differed between groups. Additionally, we used voxel-based morphometry (VBM) to detect GM-volume differences between the two groups.
Compared with the HC group, the IGA group demonstrated diffusional kurtosis parameters that were significantly less in GM of the right anterolateral cerebellum, right inferior and superior temporal gyri, right supplementary motor area, middle occipital gyrus, right precuneus, postcentral gyrus, right inferior frontal gyrus, left lateral lingual gyrus, left paracentral lobule, left anterior cingulate cortex, and median cingulate cortex. The bilateral fusiform gyrus, insula, posterior cingulate cortex (PCC), and thalamus also exhibited less diffusional kurtosis in the IGA group. MK in the left PCC and K⊥ in the right PCC were positively correlated with CIAS scores. VBM showed that IGA subjects had higher GM volume in the right inferior and middle temporal gyri, and right parahippocampal gyrus, and lower GM volume in the left precentral gyrus.
The lower diffusional kurtosis parameters in IGA suggest multiple differences in brain microstructure, which may contribute to the underlying pathophysiology of IGA. DKI may provide sensitive imaging biomarkers for assessing IGA severity.
PMCID: PMC4282196  PMID: 25344114
Internet gaming addiction; Diffusional kurtosis imaging; Gray matter; Posterior cingulate cortex
23.  Factors related to children’s caries: a structural equation modeling approach 
BMC Public Health  2014;14(1):1071.
Dental caries among preschool children is highly prevalent in many less-developed countries.
A model which explored the factors related to children’s dental caries was tested in this study using structural equation modeling. Caregivers of children aged 5 years were surveyed on their socioeconomic status, and their oral health knowledge, attitudes and practices. In addition, information on their children’s oral health practices, dental insurance and dental service utilization were collected. Examination of caries was conducted on all children who returned fully completed questionnaires.
The results showed that socioeconomic factors influenced children’s oral health practices through the impact of caregivers’ oral health knowledge and practices; that caregivers’ oral health knowledge affected children’s oral health practices through the influence of caregivers’ oral health attitudes and practices; and finally, that children’s oral health practices were linked directly to their caries.
The findings have important applications for promoting policies aimed at advancing children’s oral health.
PMCID: PMC4213540  PMID: 25316607
Child; Caregiver; Caries; Oral health knowledge; Attitude; Practice
24.  Crystal structure of 1-methyl-3-[2,2,2-tri­fluoro-1-(1-methyl-1H-indol-3-yl)-1-phenyl­eth­yl]-1H-indole 
The title compound, C26H21F3N2, was prepared by the palladium-catalysed reaction of (2,2,2-tri­fluoro­eth­yl)benzene with 1-methyl-1H-indole. The dihedral angle between the planes of the indole-ring systems is 52.13 (6)° and the N-methyl groups point away from each other. Three short intra­molecular C—H⋯F contacts are observed.
PMCID: PMC4257249  PMID: 25484800
crystal structure; 1H-indole; tri­fluoro­methyl groups; biological activity; hydrogen bonding
25.  Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers 
BMC Genomics  2014;15(1):868.
Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown.
Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium-specific enhancers derived from specific TEs.
DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-868) contains supplementary material, which is available to authorized users.
PMCID: PMC4198682  PMID: 25286960

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